The present invention relates to the use of a class of indole derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns analogues of tryptamine bearing an optionally substituted phenyl substituent at the 2-position. These compounds are selective antagonists of the human 5-HT2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including psychotic disorders such as schizophrenia.
Schizophrenia is a disorder which is conventionally treated with drugs known as neuroleptics. In many cases, the symptoms of schizophrenia can be treated successfully with so-called xe2x80x9cclassicalxe2x80x9d neuroleptic agents such as haloperidol. Classical neuroleptics generally are antagonists at dopamine D2 receptors.
Notwithstanding their beneficial antipsychotic effects, classical neuroleptic agents such as haloperidol are frequently responsible for eliciting acute extrapyramidal symptoms (movement disorders) and neuroendocrine (hormonal) disturbances. These side-effects, which plainly detract from the clinical desirability of classical neuroleptics, are believed to be attributable to D2 receptor blockade in the striatal region of the brain.
The compound (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (also known as MDL-100,907) is described in WO 91/18602. In preclinical studies, MDL-100,907 failed to induce catalepsy and failed to block apomorphine-induced stereotyped behaviour in animal models, strongly suggesting that this compound would be free from any liability to cause extrapyramidal side-effects. MDL-100,907 is currently undergoing clinical trials in schizophrenic patients and has demonstrated efficacy in a multicentre, placebo-controlled study for antipsychotic potential, with no neurological adverse effects. Pharmacologically, MDL-100,907 has been shown to be a potent antagonist of human 5-HT2A receptors, whilst being essentially devoid of activity at the human dopamine D2 receptor. It is accordingly believed that compounds which can interact selectively with the 5-HT2A receptor relative to the dopamine D2 receptor will display the beneficial level of antipsychotic activity associated with 5-HT2A receptor antagonism, whilst minimizing or even avoiding the extrapyramidal and other side-effects arising from an interaction with dopamine D2 receptors.
The compounds of use in the present invention are potent antagonists of the human 5-HT2A receptor, and are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia. The compounds of use in the invention may display more effective binding to the human 5-HT2A receptor than to the human dopamine D2 receptor, and they can therefore be expected to manifest fewer side-effects than compounds which do not discriminate in their binding affinity as between 5-HT2A and D2 receptors.
By virtue of their potent human 5-HT2A receptor antagonist activity, the compounds of use in the present invention are also effective in the treatment of neurological conditions including depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, sleep disorders such as insomnia, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA; and cardiovascular conditions including variant angina, Raynaud""s phenomenon, intermittent claudication, coronary and peripheral vasospasms, fibromyalgia, cardiac arrhythmias and thrombotic illness. They may also be generally of benefit in the inhibition of platelet aggregation, as well as in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They may further be effective in the lowering of intraocular pressure and may therefore be beneficial in treating glaucoma (cf. T. Mano et al. and H. Takaneka et al., Investigative Ophthalmology and Visual Science, 1995, vol. 36, pages 719 and 734 respectively).
Being 5-HT2A receptor antagonists, the compounds of use in the present invention may also be beneficial in preventing or reducing the toxic symptoms associated with the intake of ergovaline in animals consuming Acremonium coenophialum infected tall fescue (cf. D. C. Dyer, Life Sciences, 1993, 53, 223-228).
The preparation of a series of indole derivatives, including 3-aminoalkyl-2-phenylindoles, for pharmacological study is described in Ames et al., J. Chem. Soc., 1959, 3388-3399. No actual pharmaceutical utility is, however, ascribed to the compounds disclosed therein.
Julia et al. in Annales de l""Institut Pasteur, 1965, 343-362, describe the preparation of a number of 2-aryltryptamine derivatives, which are stated to have weak antiserotonin (rat uterus) activity.
Agarwal et al. in Indian Drugs, 1979, 209-212, and in J. Indian Chem. Soc., 1980, 57, 742-743, describe the synthesis of inter alia the compound 3- [2-(2-methylpiperidin-1-yl)ethyl]-2-phenyl-1H-indole. However, no pharmacological activity is ascribed in either publication to this specific compound.
In JP-A-55-151505 is described a class of indoles, including 3-aminoalkyl-2-phenylindole derivatives which are optionally substituted on the 2-phenyl moiety and on the benzo moiety of the indole nucleus. These compounds are stated therein to be fungicides.
Hiriyakkanavar and Siddappa in Indian J. Chem., 1966, 4, 188-190, describe the synthesis of various 5,7-dimethyl-substituted 2-phenyltryptamine derivatives, which are stated to exhibit antiserotonin activity.
Joshi et al. in Agric. Biol. Chem., 1978, 42, 1723-1726, and in Monatsh. Chem., 1980:, 111, 1343-1350, describe various fluorinated analogues of 2-phenyltryptamine. Certain of these compounds are stated to act as mild stimulants.
In none of the prior art publications referred to above, in which 2-phenyl analogues of tryptamine are described, is there any disclosure or suggestion that such compounds might be potent and selective antagonists of the human 5-HT2A receptor, nor indeed that they might be of particular benefit in the treatment in particular of neurological conditions, including psychotic disorders such as schizophrenia.
FR-A-2102282 and FR-A-2181559 describe separate series of inter alia 2-phenyltryptamine analogues, both of which are stated to possess a variety of actions on the nervous system.
The compounds of use in the present invention are potent and selective 5-HT2A receptor antagonists having a human 5-HT2A receptor binding affinity (Ki) of 100 nM or less, typically of 50 nM or less and preferably of 10 nM or less. The compounds of use in the invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity, for the human 5-HT2A receptor relative to the human dopamine D2 receptor.
The present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof: 
wherein
A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
X and Y independently represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or phenyl;
R1 represents hydrogen or C1-6 alkyl;
R2 represents hydrogen, methyl, ethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl or n-pentyl; and
R3 represents C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R2 and R3 taken together with the intervening nitrogen atom represent a group of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) or (m): 
in which the broken line represents an optional chemical bond;
Z represents oxygen, sulphur, Nxe2x80x94R6 or CR7R8;
R4 represents hydrogen, C1-6 alkyl, C1-6 alkoxy(C1-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl or aryloxy;
R5 represents hydrogen, C1-6 alkyl or C1-6 alkoxy(C1-6)alkyl;
R6 represents hydrogen, xe2x80x94COR9 or xe2x80x94CO2R9; or C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, C3-7 heterocycloalkyl(C1-6)alkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
R7 represents hydrogen, hydrocarbon, a heterocyclic group, xe2x80x94COR9 or xe2x80x94CO2R9;
R8 represents hydrogen, phenyl or acetoxy; and
R9 represents C1-6 alkyl;
for the manufacture of a medicament for the treatment and/or prevention of clinical conditions for which a selective antagonist of 5-HT2A receptors is indicated, especially psychotic disorders including schizophrenia.
The present invention also provides a method for the treatment and/or prevention of clinical conditions for which a selective antagonist of 5-HT2A receptors is indicated, especially psychotic disorders including schizophrenia, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.
A particular subset of compounds of use in the present invention comprises the compounds of formula I as depicted above, and pharmaceutically acceptable salts thereof, wherein
A, B, X, Y and R1 are as defined above;
R2 represents hydrogen, methyl or ethyl; and
R3 represents C1-6 alkyl, C3-9 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R2 and R3 taken together with the intervening nitrogen atom represent a group of formula (a) to (k) as defined above, in which
R4 represents hydrogen or C1-6 alkyl; and
Z, R5, R6, R7, R8 and R9 are as defined above.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of use in this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of use in the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of use in the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The term xe2x80x9chydrocarbonxe2x80x9d as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-9 cycloalkyl, C3-9 cycloalkyl(C1-6)alkyl, indanyl, aryl, aryl(C1-6)alkyl and aryl(C2-6)alkenyl.
The expression xe2x80x9ca heterocyclic groupxe2x80x9d as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl and heteroaryl(C1-6)alkyl groups.
Suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and 2,2-dimethylpropyl.
Suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl, 2-methylpropenyl and dimethylallyl groups.
Suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 2 carbon atoms. Typical examples include ethynyl and propargyl groups.
Suitable cycloalkyl groups include groups containing from 3 to 9 carbon atoms. Particular cycloalkyl groups are cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl.
Typical examples of C3-9 cycloalkyl(C1-6)alkyl groups include cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.
Particular indanyl groups include indan-1-yl and indan-2-yl.
Particular aryl groups include phenyl and naphthyl.
Particular aryl(C1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl, phenylbutyl and naphthylmethyl.
Typical aryl(C2-6)alkenyl groups include phenylethenyl and phenylpropenyl.
Suitable heterocycloalkyl groups include tetrahydrofuryl, tetrahydrothienyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups.
Typical C3-7 heterocycloalkyl(C1-6)alkyl groups include tetrahydrofurylmethyl, morpholinylethyl and pyrrolidinylpropyl.
Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzimidazolonyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
The expression xe2x80x9cheteroaryl(C1-6)alkylxe2x80x9d as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl and isoquinolinylmethyl.
The hydrocarbon and heterocyclic groups, as well as the substituents R3 and R6, may in turn be optionally substituted by one or more groups, preferably by one or two optional groups, selected from C1-6 alkyl, adamantyl, phenyl or halophenyl (except when R3 is C1-3 alkyl), benzyl, thiadiazolyl, halogen, C1-6 haloalkyl, C1-6 aminoalkyl, difluoromethyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, benzyloxy, OXO, C1-3 alkylenedioxy, 1,3-dioxabutylene, nitro, cyano, carboxy, C2-6 alkoxycarbonyl, C2-6 alkoxycarbonyl(C1-6)alkyl, C2-6 alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C2-6 alkylcarbonyl, arylcarbonyl, C1-6 alkylthio, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, arylsulphonyl, xe2x80x94NRvRw, xe2x80x94NRvCORw, xe2x80x94NRvCO2Rw, xe2x80x94NRvSO2Rw, xe2x80x94CH2NRvSO2Rw, xe2x80x94NHCONRvRw, xe2x80x94CONRvRw, xe2x80x94SO2NRvRw and xe2x80x94CH2SO2NRvRw, in which Rv and Rw independently represent hydrogen, C1-6 alkyl, aryl or aryl(C1-6)alkyl, or Rv and Rw together represent a C2-6 alkylene group.
When Rv and Rw together represent a C2-6 alkylene group, this group may be an ethylene, propylene, butylene, pentamethylene or hexamethylene group, preferably butylene or pentamethylene.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.
Where the compounds of use in the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds of use in the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that the use of all such isomers and mixtures thereof in any proportion is encompassed within the scope of the present invention.
Particular values for the substituent A in the compounds of formula I above include hydrogen, fluoro, trifluoromethyl and methyl, especially hydrogen.
Suitably, B represents hydrogen, fluoro, chloro, cyano, nitro, trifluoromethyl, trifluoromethoxy, methyl or methoxy.
Particular values for the substituent X include hydrogen and fluoro, especially hydrogen.
Suitably, Y represents hydrogen, fluoro, chloro, bromo, methyl, methoxy or phenyl.
Suitably, R1 represents hydrogen or methyl, especially hydrogen.
Suitably, R2 represents hydrogen, methyl or ethyl, typically hydrogen or methyl.
In one embodiment, R2 represents hydrogen. In another embodiment, R2 is methyl.
Illustrative values of R3 include methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, n-pentyl, 2-methylpropenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, phenyl, tetrahydrothienyl, piperidinyl, tetrahydrofurylmethyl, morpholinylethyl, pyrrolidinylpropyl, morpholinylpropyl and furylmethyl, any of which groups may be optionally substituted by one or more substituents.
Representative values of R3 include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclooctyl, phenyl, tetrahydrothienyl, piperidinyl, tetrahydrofurylmethyl, morpholinylethyl, pyrrolidinylpropyl and furylmethyl, any of which groups may be optionally substituted by one or more substituents.
The moiety R3 may be unsubstituted, or substituted by one or more substituents. Preferably, R3 is unsubstituted, or substituted by one or two substituents. Examples of typical substituents on the moiety R3 include benzyl, fluoro, chloro, bromo, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, oxo, 1,3-dioxabutylene and diisopropylamino.
Specific values of R3 include methyl, ethyl, fluoroethyl, trifluoroethyl, methoxyethyl, diisopropylamino-ethyl, n-propyl, fluoropropyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, n-pentyl, 2-methylpropenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, phenyl, fluorophenyl, chlorophenyl, dichlorophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, ethoxyphenyl, isopropoxyphenyl, difluoromethoxy-phenyl, trifluoromethoxy-phenyl, 1,3-dioxabutylenephenyl, tetrahydrothienyl dioxide, benzyl-piperidinyl, tetrahydrofurylmethyl, morpholinethyl, pyrrolidinylpropyl, morpholinylpropyl and furylmethyl.
Particular values of R3 include methyl, ethyl, diisopropylaminoethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclooctyl, phenyl, fluorophenyl, chlorophenyl, dichlorophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, ethoxyphenyl, isopropoxyphenyl, difluoromethoxy-phenyl, trifluoromethoxy-phenyl, 1,3-dioxabutylenephenyl, tetrahydrothienyl dioxide, benzyl-piperidinyl, tetrahydrofurylmethyl, morpholinylethyl, pyrrolidinylpropyl and furylmethyl.
In one embodiment, Z represents oxygen or sulphur. In another embodiment, Z represents CR7R8.
In a further embodiment, Z represents oxygen, sulphur or Nxe2x80x94R6. In a still further embodiment, Z represents Nxe2x80x94R6 or CR7R8. In a yet further embodiment, Z represents oxygen, sulphur or CR7R8.
Suitably, R4 represents hydrogen, methyl, methoxymethyl, pyrrolidinylmethyl or phenoxy, especially hydrogen or methoxymethyl, and more especially hydrogen. More particularly, R4 may represent hydrogen or methyl, especially hydrogen.
Suitably, R5 represents hydrogen, methyl, ethyl, n-propyl or methoxymethyl, especially hydrogen.
Illustrative values of R6 include hydrogen, acetyl and tert-butoxycarbonyl; and methyl, ethyl, n-propyl, isopropyl, allyl, cyclopentyl, cyclohexyl, benzyl, phenylethyl, phenylethenyl, morpholinylethyl, pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl and benzofuryl, any of which groups may be optionally substituted by one or more substituents.
Representative values of R6 include hydrogen, acetyl and tert-butoxycarbonyl; and methyl, ethyl, propyl, allyl, cyclohexyl, benzyl, phenylethyl, phenylethenyl, morpholinylethyl, pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl and benzofuryl, any of which groups may be optionally substituted by one or more substituents.
The moiety R6 may be unsubstituted, or substituted by one or more substituents. Preferably, R6 is unsubstituted, or substituted by one or two substituents. Examples of typical substituents on the moiety R6 include methyl, ethyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, benzyloxy, methylenedioxy, nitro, cyano, acetoxy, methylthio, dimethylamino, diethylamino, dipropylamino, N-methyl-N-phenylaminocarbonyl and pyrrolidinylcarbonyl. More specific examples of typical substituents on the moiety R6 include methyl, ethyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, benzyloxy, methylenedioxy, nitro, cyano, acetoxy, methylthio, dimethylamino, diethylamino, N-methyl-N-phenylaminocarbonyl and pyrrolidinylcarbonyl.
Specific values for the moiety R6 include hydrogen, acetyl, tert-butoxycarbonyl, methyl, benzyloxymethyl, N-methyl-N-phenylaminocarbonyl-methyl, pyrrolidinylcarbonyl-methyl, ethyl, methoxyethyl, acetoxyethyl, dimethylamino-ethyl, diethylamino-ethyl, dipropylamino-ethyl, dimethylamino-propyl, isopropyl, allyl, cyclopentyl, cyclohexyl, benzyl, tert-butylbenzyl, diphenylmethyl, (chlorophenyl)(phenyl)methyl, di(fluorophenyl)methyl, di(chlorophenyl)methyl, chlorobenzyl, methylenedioxy-benzyl, 1-phenylethyl, 2-phenylethyl, chlorophenyl-ethenyl, cyanophenyl-ethenyl, morpholinylethyl, pyridinyl, trifluoromethyl-pyridinyl, (chloro)(trifluoromethyl)pyridinyl, trifluoromethyl-quinolinyl, isoquinolinyl, pyrimidinyl, trifluoromethyl-pyridimidinyl and benzofuryl.
Particular values of R6 include hydrogen, acetyl, tert-butoxycarbonyl, methyl, benzyloxymethyl, N-methyl-N-phenylaminocarbonyl-methyl, pyrrolidinylcarbonyl-methyl, ethyl, methoxyethyl, acetoxyethyl, diethylamino-ethyl, dimethylamino-propyl, allyl, cyclohexyl, benzyl, tert-butylbenzyl, diphenylmethyl, (chlorophenyl)(phenyl)methyl, di(fluorophenyl)methyl, di(chlorophenyl)methyl, chlorobenzyl, methylenedioxy-benzyl, phenylethyl, chlorophenyl-ethenyl, cyanophenyl-ethenyl, morpholinylethyl, pyridinyl, trifluoromethyl-pyridinyl, (chloro)(trifluoromethyl)pyridinyl, trifluoromethyl-quinolinyl, isoquinolinyl, pyrimidinyl, trifluoromethyl-pyridimidinyl and benzofuryl.
Suitable values of R7 include hydrogen, C2-6 alkylcarbonyl and C2-6 alkoxycarbonyl; and C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, aryl(C1-6)alkyl1, aryl(C2-6)alkenyl, C3-7 heterocycloalkyl(C1-6)alkyl and heteroaryl, any of which groups may be optionally substituted by one or more substituents.
Representative values of R7 include hydrogen, acetyl and tert-butoxycarbonyl; and methyl, ethyl, propyl, allyl, cyclohexyl, phenyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylethenyl, phenylpropenyl, morpholinylethyl, pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, benzofuryl and benzimidazolonyl, any of which groups may be optionally substituted by one or more substituents.
The moiety R7 may be unsubstituted, or substituted by one or more substituents. Preferably, R7 is unsubstituted, or substituted by one or two substituents. Examples of typical substituents on the moiety R7 include methyl, ethyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, benzyloxy, methylenedioxy, nitro, cyano, acetoxy, methylthio, dimethylamino, diethylamino, N-methyl-N-phenylaminocarbonyl and pyrrolidinylcarbonyl.
Specific values for the moiety R7 include hydrogen, acetyl, tert-butoxycarbonyl, methyl, benzyloxymethyl, N-methyl-N-phenylaminocarbonyl-methyl, pyrrolidinylcarbonyl-methyl, ethyl, methoxyethyl, acetoxyethyl, diethylamino-ethyl, dimethylamino-propyl, allyl, cyclohexyl, phenyl, methylphenyl, dimethylphenyl, ethylphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, trifluoromethyl-phenyl, (chloro)(trifluoromethyl)phenyl, bis(trifluoromethyl)phenyl, methoxyphenyl, (dichloro)(methoxy)phenyl, dimethoxyphenyl, trimethoxyphenyl, ethoxyphenyl, methylenedioxy-phenyl, nitrophenyl, (dinitro)(trifluoromethyl)phenyl, cyanophenyl, dicyanophenyl, methylthiophenyl, benzyl, tert-butylbenzyl, diphenylmethyl, (chlorophenyl)(phenyl)methyl, di(fluorophenyl)methyl, di(chlorophenyl)methyl, chlorobenzyl, methylenedioxy-benzyl, phenylethyl, 3,3-diphenylpropyl, 4-phenylbut-2-yl, chlorophenyl-ethenyl, cyanophenyl-ethenyl, phenylpropenyl, morpholinylethyl, pyridinyl, trifluoromethyl-pyridinyl, (chloro)(trifluoromethyl)pyridinyl, trifluoromethyl-quinolinyl, isoquinolinyl, pyrimidinyl, trifluoromethyl-pyridimidinyl, benzofuryl and benzimidazolonyl.
In relation to formula (c) above in which Z represents CR7R8, the moiety R7 suitably represents hydrogen, methyl, benzyloxymethyl, phenyl, methoxyphenyl, benzyl, phenylethyl or benzimidazolonyl. More particularly, R7 in this context may suitably represent hydrogen, benzyloxymethyl, benzyl, phenylethyl or benzimidazolonyl.
In relation to formula (e) above, the moiety R7 suitably represents methylenedioxy-phenyl, chlorophenyl-ethenyl, cyanophenyl-ethenyl or benzofuryl.
In relation to formula (f) above, the moiety R7 suitably represents benzyl.
Suitably, R8 represents hydrogen.
Suitably, R9 represents methyl or tert-butyl.
Specific compounds of use in the present invention include:
3-[2-(N,N-dimethylamino)ethyl]-2-phenyl-1H-indole;
3-[2-(N,N-diethylamino)ethyl]-2-phenyl-1H-indole;
2-phenyl-3-[2-(pyrrolidin-1-yl)ethyl]-1H-indole;
2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole;
3-[2-(2-methylpiperidin-1-yl)ethyl]-2-phenyl-1H-indole;
3-[2-homopiperidin-1-yl)ethyl]-2-phenyl-1H-indole;
3-[2-(morpholin-4-yl)ethyl]-2-phenyl-1H-indole ;
2-(4-fluorophenyl)-3-[2-(piperidin-1-yl)ethyl]-1H-indole;
and pharmaceutically acceptable salts thereof.
Certain compounds falling within the definition of formula I above are novel. Accordingly, in a further aspect, the present invention provides a compound of formula I as defined above, or a salt thereof, wherein B represents trifluoromethyl or trifluoromethoxy.
In another aspect, the present invention provides a compound of formula I as defined above, or a salt thereof, wherein Y represents phenyl.
In another aspect, the present invention provides a compound of formula I as defined above, or a salt thereof, provided that:
(i) when A and B independently represent hydrogen, halogen, cyano, nitro, alkyl or alkoxy, and X and Y independently represent hydrogen, halogen, alkyl or alkoxy, then either R3 does not represent alkyl, or R2 and R3 taken together with the intervening nitrogen atom do not represent piperidin-1-yl or morpholin-4-yl; and
(ii) when A, B, X, Y and R1 each represents hydrogen, then R2 and R3 taken together with the intervening nitrogen atom do not represent pyrrolidin-1-yl, 2-methylpiperidin-1-yl or homopiperidin-1-yl.
Particular sub-classes of novel compounds in accordance with the present invention are represented by the compounds of formula IA and IB, and salts thereof: 
wherein R2 and R3 are as defined above.
Specific compounds in accordance with the present invention include those compounds disclosed in the accompanying Examples, with the exception of Example Nos. 1, 9, 22, 34, 36, 38, 49 and 55.
The invention also provides pharmaceutical compositions comprising one or more of the novel compounds according to the invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. An erodible polymer containing the active ingredient may be envisaged. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Favoured unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of schizophrenia, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
If desired, the compounds of use in this invention may be co-administered with another anti-schizophrenic medicament, for example one producing its effects via dopamine D2 and/or D4 receptor subtype blockade. In such circumstances, an enhanced anti-schizophrenic effect may be envisaged without a corresponding increase in side-effects such as those caused by, for example, D2 receptor subtype blockade; or a comparable anti-schizophrenic effect with reduced side-effects may alternatively be envisaged. Such co-administration may be desirable where a patient is already established on an anti-schizophrenic treatment regime involving conventional anti-schizophrenic medicaments. Suitable anti-schizophrenic medicaments of use in combination with the compounds according to the present invention include haloperidol, chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chloroprothixene, thiothixene, clozapine, olanzapine, pimozide, molindone, loxapine, sulpiride, risperidone, xanomeline, fananserin and ziprasidone, and pharmaceutically acceptable salts thereof.
The compounds of formula I above, including the novel compounds according to the present invention, may be prepared by a process which comprises reacting a compound of formula II with a compound of formula III: 
wherein A, B, X, Y, R1, R2 and R3 are as defined above, L1 represents a suitable leaving group and Rp represents a hydrogen atom, an amino-protecting group or an attached resin moiety; followed, where necessary, by removal of the amino-protecting group or attached resin moiety Rp.
The leaving group L1 is suitably an alkylsulphonyloxy or arylsulphonyloxy moiety such as trifluoromethanesulphonyloxy (triflyloxy) or p-toluenesulphonyloxy (tosyloxy), preferably triflyloxy.
Where Rp represents an amino-protecting group, this is suitably a carbamoyl moiety, e.g. tert-butoxycarbonyl (BOC), which can readily be removed as required by treatment with acid, typically trifluoroacetic acid, or with base, e.g. sodium methoxide in methanol.
Where Rp represents an attached resin moiety, this is suitably a polymeric moiety such as the commercially available WANG resin, whereby the substituent Rp represents (4-benzyloxycarbonyl) phenoxymethylcopoly(styrene-1% divinylbenzene). The WANG resin can be conveniently removed at the appropriate stage by treatment with pyrrolidine at an elevated temperature, typically in a solvent such as N,N-dimethylformamide.
The reaction between compounds II and III is conveniently effected by stirring in an appropriate solvent, e.g. dichloromethane, 1,2-dichloroethane or N,N-dimethylformamide, optionally under basic conditions, for example in the presence of potassium carbonate.
In an alternative procedure, the compounds of formula I above, including the novel compounds according to the invention, may be prepared by a process which comprises reacting a compound of formula IV with a compound of formula V: 
wherein A, B, X, Y, R1, R2, R3 and Rp are as defined above; one of M1 and M2 represents a suitable leaving group, and the other represents a boronic acid moiety xe2x80x94B(OH)2 or a 1-4 alkyl ester or anhydride thereof; in the presence of a transition metal catalyst; followed, where necessary, by removal of the amino-protecting group or attached resin moiety Rp.
The leaving group M1 or M2 is suitably a halogen atom, e.g. bromine.
The transition metal catalyst of use in the reaction between compounds IV and V is suitably tetrakis(triphenylphosphine)palladium (0);. The reaction is conveniently carried out in an inert solvent such as ethanolic toluene, aqueous tetrahydrofuran or aqueous 1,2-dimethoxyethane, advantageously in the presence of a base such as sodium acetate or sodium carbonate, optionally in the presence of lithium chloride, and typically at an elevated temperature.
Where L1 represents triflyloxy or tosyloxy, the intermediates of formula II above may be prepared by triflylation or tosylation of the corresponding 3-(2-hydroxyethyl)indole derivative using standard techniques, e.g. by treatment with triflic anhydride (Tf2O), typically in a solvent such as dichloromethane or 1,2-dichloroethane and optionally in the presence of a base such as 2,6-di-tert-butyl-4-methylpyridine. The hydroxy compound may in turn be prepared by reaction of a compound of formula V as defined above with a compound of formula VI: 
wherein X, Y, R1, Rp and M1 are as defined above, and Rq represents hydrogen or a hydroxy-protecting group; under conditions analogous to those defined above for the reaction between compounds IV and V; followed, where necessary, by removal of the hydroxy-protecting group Rq.
Where Rq represents a hydroxy-protecting group, this is ideally a tetrahydro-2H-pyran-2-yl moiety, which can conveniently be removed as necessary under acidic conditions, for example by treatment with pyridinium p-toluenesulphonate (PPTS) in a suitable solvent, e.g. ethanol or a mixture of ethanol and 1,2-dichloroethane.
The intermediates of formula IV may be prepared by reacting a compound of formula III as defined above with a compound of formula VII: 
wherein X, Y, R1, Rp, L1 and M1 are as defined above; under conditions analogous to those described above for the reaction between compounds II and III.
Where L1 represents triflyloxy or tosyloxy, the intermediates of formula VII may be prepared by triflylation or tosylation of the appropriate compound of formula VI wherein Rq represents hydrogen, using standard techniques.
In another procedure, the compounds of formula I above, including the novel compounds according to the invention, may be prepared by a process which comprises reacting a compound of formula III as defined above with a compound of formula VIII: 
wherein A, B, X, Y, R1 and Rp are as defined above; in the presence of a reducing agent; followed, where necessary, by removal of the amino-protecting group or attached resin moiety Rp.
A suitable reducing agent for use in the reaction between compounds III and VIII is sodium triacetoxyborohydride. The reaction is conveniently effected in the presence of acetic acid, typically in an inert solvent such as 1,2-dichloroethane.
In a further procedure, the compounds of formula I above, including the novel compounds according to the invention, may be prepared by a process which comprises reacting a compound of formula IX or an acid addition salt thereof, typically the hydrochloride salt, with a compound of formula X: 
wherein A, B, X, Y, R1, R2 and R3 are as defined above.
The reaction between compounds IX and X, which is an example of the well-known Fischer indole synthesis, is suitably effected by stirring in ethanol at 25xc2x0 C., followed by heating in trifluoroacetic acid at 70xc2x0 C.
In a still further procedure, the compounds of formula I above, including the novel compounds according to the invention, may be prepared by a process which comprises reacting a compound of formula XI with a compound of formula XII (cf Larock and Yum, J. Am. Chem. Soc., 1991, 113, 6689): 
wherein A, B, X, Y, R1, R2 and R3 are as defined above; in the presence of a transition metal catalyst.
Similarly, the intermediates of formula II, or their hydroxy precursors, and the intermediates of formula VIII may be prepared by reacting a compound of formula XI as defined above with the appropriate compound of formula XIII or XIV: 
wherein A, B and R1 are as defined above, and L11 corresponds to the moiety L1 or represents hydroxy; in the presence of a transition metal catalyst.
The transition metal catalyst employed in the reaction between compound XI and compound XII, XIII or XIV is suitably a palladium-containing catalyst. Typical catalysts include palladium(II) acetate, optionally in the presence of triphenylphosphine, and dichlorobis(triphenylphosphine)palladium(II). A preferred catalyst is dichlorobis(triphenylphosphine)palladium(II).
The transition metal catalysed indole formation reaction between compound XI and compound XII, XIII or XIV is advantageously carried out under basic conditions. Typical basic reagents of use in the reaction include sodium carbonate, potassium carbonate, sodium acetate or potassium acetate, optionally in the presence of lithium chloride or tetra-n-butylammonium chloride; and tetramethylguanidine. A preferred base is tetramethylguanidine. The reaction is conveniently effected in a polar aprotic organic solvent such as N,N-dimethylformamide, typically at an elevated temperature, e.g. a temperature in the region of 80-110xc2x0 C.
Where they are not commercially available, the starting materials of formula III, V, VI, IX, X, XI, XII, XIII and XIV may be prepared by procedures analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be appreciated that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I using techniques known from the art.
Where the above-described processes for the preparation of the compounds of use in the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following Examples illustrate the preparation of compounds of use in the invention.
The compounds useful in this invention potently inhibit [3H]-ketanserin binding to the human 5-HT2A receptor expressed in clonal cell lines. Moreover, those compounds of use in the invention which have been tested display a selective affinity for the 5-HT2A receptor relative to the dopamine D2 receptor.
The compounds of the accompanying Examples were all found to possess a Ki value for displacement of [3H]-ketanserin from the human 5-HT2A receptor, when expressed in Chinese hamster ovary (CHO) clonal cell lines, of 100 nM or less.